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PLUMB’S THERAPEUTICS BRIEF h Rx SOLUTIONS h PEER REVIEWED

ChronicDrugs UpperUsed to Respiratory Manage UrinaryTract Disease Incontinence in a Cat in Dogs & Cats Margie Scherk, DVM, DABVP (Feline) catsiNK Julie KathleenVancouver, Byron, BC, DVM, Canada MS, DACVIM The Ohio State University

REDLIGHT GREEN LIGHT h PEER REVIEWED

Urinary incontinence is a common presenting complaint primar- Following are therapeutic targets for the various causes of ily affecting dogs and occasionally cats. The most common incontinence. cause of urinary incontinence is urethral sphincter mechanism incompetence (USMI), which typically affects spayed female DRUGS TO MANAGE STORAGE DISORDERS dogs and occasionally male dogs. Other causes include disor- a-Adrenergic Drug ders such as urine retention and bladder outflow obstruction, Phenylpropanolamine which are more common in male dogs. Phenylpropanolamine is a nonselective α-agonist that also has some β-agonist effects. It indirectly increases urethral smooth Therapeutic objectives include treating signs of incontinence- muscle tone and may also induce relaxation of the detrusor mus- related disorders such as storage disorders (eg, USMI, ectopic cle via β-adrenergic effects. Its nonselectivity may lead to stimu- ureter, overactive bladder) and emptying disorders (eg, lation of vasoconstriction and overall sympathetic activation. detrusor-urethral dyssynergia, functional obstruction, ure- throspasm, detrusor atony, neurogenic upper motor neuron Formulation → Oral bladder). Goals for treating storage disorders include increas- ing urethral sphincter smooth and striated muscle tone, Dose (dogs, cats) → 1-2 mg/kg PO q8-12h1 increasing bladder compliance, and decreasing intravesicular pressures during filling and storage. Goals for treating empty- Key Points ing disorders include decreasing urethral sphincter smooth h Dose escalation or increased frequency over time may be and striated muscle tone, increasing detrusor contraction, and necessary. reducing postvoid residual volume. USMI = urethral sphincter mechanism incompetence

December 2017 Plumb’s Therapeutics Brief 53 PLUMB’S THERAPEUTICS BRIEF h Rx SOLUTIONS h PEER REVIEWED

h Adverse effects include hypertension, restlessness, Diethylstilbestrol decreased appetite, and aggression.2 Diethylstilbestrol is a potent, synthetic, nonsteroidal estrogen h Should be used with caution in patients that are predisposed that improves continence by increasing the number and to hypertension because of comorbid conditions (eg, kidney sensitivity of α-receptors in the urethral . It disease, hyperadrenocorticism, hyperthyroidism)3 has a trophic effect on periurethral tissues and vasculature. h May increase agitation in patients with anxiety disorders Formulation → Not commercially available; must be compounded Estrogens Estriol Dose (dogs only) → 0.5-1.0 mg/dog PO q24h for 3 to 5 days, Estriol is a naturally occurring estrogen with affinity for both then q7d1 types of estrogen receptors. It can improve continence by Administration interval should be titrated to effect.1 increasing the number and sensitivity of α-receptors in the urethral smooth muscle, and it has a trophic effect on peri- Key Points 4 urethral tissues and vasculature. h Reported efficacy of approximately 65% complete and 23% improved continence in female dogs6 Formulation → Oral h Although estrogens can lead to bone marrow suppression, this has not been reported at recommended doses.7 Dose (dogs only) → 2 mg/dog PO q24h for 14 days, then reduce h Adverse effects include vulvar or mammary swelling, attrac- in 0.5-mg increments q7d to lowest effective dose1 tiveness to males, lethargy, vomiting, and diarrhea. • Most patients respond to dose reduction. Key Points h Should not be used in intact females h Efficacy in female dogs reported as 82% to 92% improved h Use in males may lead to prostatic metaplasia. 5 or complete continence h Overdose can lead to bone marrow suppression. h Although estrogens can lead to bone marrow suppression, h Should not be used in cats this effect has not been reported when this drug is used at the recommended doses. Tricyclic h Adverse effects include vulvar or mammary swelling, attractiveness to males, lethargy, vomiting, and diarrhea. Imipramine is a norepinephrine reuptake inhibitor and poten- • Most patients respond to dose reduction. tial that indirectly increases α-receptor stimu- h Should not be used in intact females lation in the urethral smooth muscle. This drug may increase h Use in males may lead to prostatic metaplasia. bladder relaxation. h Overdose can lead to bone marrow suppression. h Should not be used in cats Formulation → Oral

Dose (dogs) → 5-15 mg/dog PO q12h1 Dose (cats) → 2.5-5 mg/cat PO q12h1

Key Points Diethylstilbestrol use h Imipramine has complex mechanisms of action and appears in males may lead to to act through both stimulation of the sympathetic nervous system and inhibition of the parasympathetic nervous system. prostatic metaplasia. h Evidence of efficacy in the treatment of urinary storage disorders in dogs and cats is lacking. • Rationale for use is extrapolated from in vitro studies and clinical evidence of the drug’s effect in humans and healthy USMI = urethral sphincter mechanism incompetence dogs.

54 Plumb’s Therapeutics Brief December 2017 h Adverse effects include vomiting, diarrhea, hyperexcitability, • Treatment should be repeated as needed when clinical seizure, and sedation. signs return. h May lower seizure threshold in epileptic patients h Most commonly used to treat endocrine diseases in ferrets h Should not be coadministered with monoamine oxidase and suppress egg formation in birds inhibitors h Little is known about adverse effects in dogs and cats.

Testosterone Analog Antimuscarinic & Spasmolytic Drugs Testosterone Cypionate Testosterone is thought to improve urethral smooth muscle tone; Oxybutynin has direct antimuscarinic effects on the smooth however, evidence of the mechanism and its efficacy in the treat- muscle of the bladder without affecting the smooth muscle of ment of urinary tract disorders in dogs and cats is lacking. the vasculature.

Formulation → Parenteral for IM injection Formulation → Oral

Dose (dogs only) → 2.2 mg/kg IM q30-60d1 Dose (dogs) → 0.2 mg/kg PO q8-12h or 1.25-3.75 mg/dog PO q8-12h1 Key Points Dose (cats; extra-label) → 0.5-1.25 mg/cat PO q8-12h1 h Anecdotally considered to be less effective than phenylpro- panolamine in male dogs with USMI Key Points h Adverse effects include perianal adenoma and prostate h Primarily used in cases of suspected overactive bladder or enlargement in male patients and clitoral hypertrophy, detrusor instability masculinization, and aggression in female patients. h Also acts as an and reduces maximum filling h Should not be used in patients with prostatic carcinoma and and emptying bladder pressures11 should be used with caution in patients with renal, cardiac, h Adverse effects include diarrhea, , hypersaliva- or hepatic disease tion, urine retention, and sedation. h May decrease insulin needs in diabetic patients1 h Use with other sedatives may increase effect. h Should be used with caution in patients with hypotension Gonadotropin-Releasing Hormone (GnRH) Analog Leuprolide Acetate Propantheline Leuprolide acetate is a GnRH analog that suppresses both Propantheline is an antimuscarinic agent that has effects on the follicle-stimulating hormone and luteinizing hormone increases smooth muscle of the bladder and may reduce spasm related to after ovariohysterectomy in dogs. Some evidence shows that detrusor hyperreflexia and associated urinary incontinence. the alteration of these hormones may play a larger role in USMI development as compared with a change in estrogen levels.8 Formulation → Oral; injectable form available in Australia This drug does not appear to affect urethral pressures but can improve bladder relaxation and compliance.9,10 Dose (dogs) → 7.5-30 mg/dog PO q8-24h1 Dose (cats) → 5-7.5 mg/cat PO q8-72h; lowest effective dose Formulation → Depot injection should be used1 Immediate-release form should be avoided. Key Points Dose (dogs) → 20-30 mg IM q3mo10 h Variable absorption of the oral formulation in small animals; Doses are extrapolated from the literature.10 No standard dose must be adjusted for each patient. dose regimen has been established. h Should not be used if urinary obstruction or urine retention is suspected Key Points h Adverse effects include dry mouth, tachycardia, ileus, and con- h Effects may last longer than 3 months. stipation; vomiting and hypersalivation may be seen in cats.1

December 2017 Plumb’s Therapeutics Brief 55 PLUMB’S THERAPEUTICS BRIEF h Rx SOLUTIONS h PEER REVIEWED

DRUGS TO MANAGE EMPTYING DISORDERS h Oral bioavailability in dogs is about one-third of that in α-Adrenergic Blocking Drugs humans.17 & Smooth Muscle Relaxants • Bioavailability may be increased when administered on an Prazosin empty . h Prazosin is a nonselective α1-inhibitor used to block α-receptors May take several days for effect in the urethral smooth muscle and treat functional urethral h High doses may lead to hypotension. obstruction.12 h Sustained-release formulations should not be crushed.

Formulation → Oral Phenoxybenzamine Phenoxybenzamine is a pure α-adrenergic blocker used to Dose (dogs) → 1 mg/dog PO q8-12h for dogs weighing <15 kg; reduce urethral pressures and treat hypertension. 2 mg/dog PO q8-12h for dogs weighing >15 kg1 Dose (cats) → 0.25-1 mg/cat PO q8-12h1 Formulation → Oral

1 Key Points Dose (dogs) → 0.25 mg/kg PO q12h or 5-20 mg/dog PO q12h 1 h The nonselective nature of prazosin also leads to vasodila- Dose (cats) → 2.5-7.5 mg/cat PO q12-24h tion and decreased vascular resistance. h Hypotension is the primary adverse effect. Key Points • Patients should be monitored with each dose increase. h Cost is significantly higher as compared with other • Caution should be used when administering with α-adrenergic blockers. β-blocking agents and calcium channel blockers, h Often used to reduce pheochromocytoma-induced as prazosin may induce significant hypotension. hypertension h Has been found to be more effective than phenoxyben- h Blood pressure should be monitored. zamine at decreasing urethral pressures13 h Adverse effects include hypotension, weakness, nausea, h Rates of urethral reobstruction in cats treated with prazosin miosis, and sodium retention. were lower than in those treated with phenoxybenzamine.14 h Should be used with caution in patients with cardiac disease h Prazosin may also be effective in treating ureterospasm in or other conditions predisposed to hypotension cases of ureteral obstruction or ureteritis.15 Skeletal Muscle Relaxants Tamsulosin

Tamsulosin is a selective α1a-adrenergic blocker that is more selective to the urinary tract (ie, prostatic urethra, bladder Diazepam is a used for relaxation of primarily neck) and thus has more limited cardiovascular side effects. skeletal muscle in the urethra in dogs with functional urethral obstruction. Formulation → Oral Formulation → Oral, injectable Dose (dogs) → 0.1-0.2 mg/10 kg (up to 0.4-mg total dose) PO q12-24h1 Dose (dogs) → 2-10 mg/dog PO 30 minutes before voiding 1 Dose (cats) → 0.004-0.006 mg/kg PO q12-24h1 (≤3 times a day)

Key Points Key Points h Effectively inhibits hypogastric nerve-induced urethral pres- h Serum half-life in dogs and cats is significantly shorter than 1 sure rise in dogs without clinically significant vasodilation in humans. and hypotension16 h Adverse effects include CNS depression, appetite stimula- h May be useful in treating ureterospasm associated with tion, and sedation. ureteritis or ureteroliths15 h May cause disinhibition in aggressive patients

56 Plumb’s Therapeutics Brief December 2017 h Oral form should not be used in cats, as there is significant level of the spinal cord. It has been shown to reduce urethral potential for hepatotoxicity. striated (skeletal) muscle sphincter tone in dogs.20 h Should be used carefully in debilitated patients or those with liver dysfunction Formulation → Oral

Alprazolam Dose (dogs only) → 1-2 mg/kg PO q8h Alprazolam is a benzodiazepine that produces sedation, anxioly- sis, and skeletal muscle relaxation. It may be used to relax the Key Points skeletal muscle of the urethra in patients with urethrospasm; h Should be gradually discontinued to reduce risk for psycho- however, no data on its use in this manner in either dogs or cats motor effects (eg, seizures, hallucinations) has been published. h Adverse effects include sedation, weakness, or GI cramping. h Narrow margin of safety in dogs and should not be used in cats Formulation → Oral • Should be used with caution in patients with seizure disorders

Dose (dogs) → 0.02-0.05 mg/kg PO q6-12h1 Dose (cats) → 0.125-0.25 mg/cat PO q8-24h1 Dantrolene is a direct-acting that has been Doses extrapolated from use used to treat patients that have functional urethral obstruc- tion. Because of the availability of more effective and safer Acepromazine muscle relaxants, dantrolene is not recommended as a first- Acepromazine is a that has antispasmodic and line treatment for detrusor-urethral dyssynergia. α-adrenergic blocking effects. It is used in dogs and cats with functional urethral obstruction. Formulation → Oral; injectable is available but not practical for veterinary use Formulation → Oral, injectable Dose (dogs) → 1-5 mg/kg PO q8-12h1 Dose (dogs, cats) → 0.55-2.2 mg/kg PO q6-12h or to effect1 Dose (cats) → 0.5-2 mg/kg PO q12h1

Key Points Key Points h Has been shown to significantly decrease preprostatic and h May be less effective than prostatic urethral pressures in intact male cats18 • Several studies have indicated its effect on striated muscle h Dose should be reduced in patients with possible breed- is poor.21 related MDR1 mutations (eg, collies, Shetland sheepdogs, h Adverse effects include hepatotoxicity, weakness, and Australian shepherds).1,19 sedation. h Adverse effects include hypotension and prolapse of the h Should not be used in patients with hepatic dysfunction nictitans. h Should be used with caution in patients with cardiac disease h Should not be used in patients with hypotension, volume depletion, or shock Agent h Should be used carefully in patients with cardiac disease or hepatic dysfunction Bethanechol is a cholinergic that directly stimulates musca- h Caution: Dose should be reduced in patients with possible rinic receptors in the detrusor smooth muscle of the bladder. breed-related MDR1 mutations (eg, collies, Shetland sheep- dogs, Australian shepherds).1,19 Formulation → Oral Only the oral formulation is commercially available in the Baclofen United States; injectable formulations may be available out- Baclofen is a skeletal muscle relaxant that appears to act at the side the United States or through compounding pharmacies.

December 2017 Plumb’s Therapeutics Brief 57 PLUMB’S THERAPEUTICS BRIEF h Rx SOLUTIONS h PEER REVIEWED

Dose (dogs) → 2.5-25 mg/dog PO q8h1 2. Byron JK, March PA, Chew DJ, DiBartola SP. Effect of phenylpropanolamine 1 and pseudoephedrine on the urethral pressure profile and continence Dose (cats) → 1.25-7.5 mg/cat PO q8h scores of incontinent female dogs. J Vet Intern Med. 2007;21(1):47-53. 3. Segev G, Westropp JL, Kulik C, Lavy E. Changes in blood pressure following escalating doses of phenylpropanolamine and a suggested protocol for Key Points monitoring. Can Vet J. 2015;56(1):39-43. h May not be effective in patients with chronic bladder over- 4. Skala CE, Petry IB, Albrich SB, Puhl A, Naumann G, Koelbl H. The effect of hormonal status on the expression of estrogen and proges- distension resulting from loss of smooth muscle tight junctions terone receptor in vaginal wall and periurethral tissue in urogynecological h Vomiting, diarrhea, decreased appetite, hypersalivation, patients. Eur J Obstet Gynecol Reprod Biol. 2010;153(1):99-103. 5. Mandigers RJ, Nell T. Treatment of bitches with acquired urinary and other SLUD (salivation, lacrimation, urination, defeca- incontinence with oestriol. Vet Rec. 2001;149(25):764-767. tion)-like effects may be seen at recommended doses. 6. Nendick PA, Clark WT. Medical therapy of urinary incontinence in ovariectomised bitches: a comparison of the effectiveness of h Overdose can lead to bradycardia, hypotension, and/or diethylstilboestrol and pseudoephedrine. Aust Vet J. 1987;64(4):117-118. increased respiratory secretions. 7. Sontas HB, Dokuzeylu B, Turna O, Ekici H. Estrogen-induced myelotoxicity in dogs: a review. Can Vet J. 2009;50(10):1054-1058. h Should not be used in patients with untreated urethral 8. Reichler IM, Pfeiffer E, Piché CA, et al. Changes in plasma gonadotropin obstruction or questionable bladder wall integrity concentrations and urethral closure pressure in the bitch during the 12 months following ovariectomy. Theriogenology. 2004;62(8):1391-1402. 9. Reichler IM, Barth A, Piché CA, et al. Urodynamic parameters and plasma Prokinetic Agent LH/FSH in spayed beagle bitches before and 8 weeks after GnRH depot analogue treatment. Theriogenology. 2006;66(9):2127-2136. 10. Reichler IM, Jöchle W, Piché CA, Roos M, Arnold S. Effect of a long acting Cisapride is a 5-HT4-receptor agonist that indirectly leads to GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to sphincter mechanism release and smooth muscle (eg, GI, detrusor) incompetence in bitches. Theriogenology. 2006;66(5):1227-1236. contraction. 11. Yamamoto T, Koibuchi Y, Miura S, et al. Effects of vamicamide on functions in conscious dog and rat models of urinary frequency. J Urol. 1995;154(6):2174-2178. Formulation → Must be compounded; no commercial products 12. Haagsman AN, Kummeling A, Moes ME, Mesu SJ, Kirpensteijn J. Comparison of terazosin and prazosin for treatment of vesico-urethral are available in the United States, Europe, or India. reflex dyssynergia in dogs. Vet Rec. 2013;173(2):41. 13. Fischer JR, Lane IF, Cribb AE. Urethral pressure profile and hemodynamic 1 effects of phenoxybenzamine and prazosin in non-sedated male beagle Dose (dogs) → 0.1-0.5 mg/kg PO q8-12h dogs. Can J Vet Res. 2003;67(1):30-38. Dose (cats) → 2.5-7.5 mg/cat PO q8-12h1 14. Hetrick PF, Davidow EB. Initial treatment factors associated with feline urethral obstruction recurrence rate: 192 cases (2004-2010). J Am Vet Med Assoc. 2013;243(4):512-519. Key Points 15. Kobayashi S, Tomiyama Y, Hoyano Y, et al. Mechanical and gene expression of alpha(1)-adrenoceptor subtypes in dog intravesical ureter. . h May help increase bladder contraction and reduce residual 2009;74(2):458-462. urine volume22 16. Ohtake A, Sato S, Saitoh C, Yuyama H, Sasamata M, Miyata K. Effects of tamsulosin on hypogastric nerve stimulation-induced intraurethral h Commonly used to treat cats with pressure elevation in male and female dogs under anesthesia. Eur J h Removed from commercial manufacture in 2002 because of Pharmacol. 2004;497(3):327-334. 23 17. Matsushima H, Kamimura H, Soeishi Y, Watanabe T, Higuchi S, Tsunoo M. arrhythmias seen in humans Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride • These effects are not well demonstrated in dogs and cats. in rats, dogs, and humans. Drug Metab Dispos. 1998;26(3):240-245. 18. Marks SL, Straeter-Knowlen IM, Moore M, Speth R, Rishniw M, Knowlen h Adverse effects include diarrhea, vomiting, and ataxia. GG. Effects of acepromazine maleate and phenoxybenzamine on urethral • Administration should start at low end of dose range and pressure profiles of anesthetized, healthy, sexually intact male cats. Am J Vet Res. 1996;57(10):1497-1500. titrate up to avoid these effects. 19. Deshpande D, Hill KE, Mealey KL, Chambers JP, Gieseg MA. The effect of the h Cisapride is metabolized by the cytochrome P450 CYP3A canine ABCB1-1∆ mutation on sedation after intravenous administration of acepromazine. J Vet Intern Med. 2016;30(2):636-641. and should be used with caution in patients receiving 20. Teague CT, Merrill DC. Effect of baclofen and dantrolene on bladder CYP3A-inhibitors (eg, azole antifungals, cimetidine, stimulator-induced detrusor-sphincter dyssynergia in dogs. Urology. 1978;11(5):531-535. diltiazem, chloramphenicol). 21. Harris JD, Benson GS. Effect of dantrolene sodium on canine bladder h Dose reduction may be necessary in patients that have contractility. Urology. 1980;16(2):229-231. 22. Madeiro AP, Rufino AC, Sartori MGF, Baracat EC, De Lima GR, Girão MJBC. hepatic dysfunction. The effects of bethanechol and cisapride on urodynamic parameters h Use should be avoided in patients with GI obstruction. n in patients undergoing radical hysterectomy for cervical cancer. A randomized, double-blind, placebo-controlled study. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(3):248-252. References 23. Tack J, Camilleri M, Chang L, et al. Systematic review: cardiovascular safety 1. Plumb DC, ed. Plumb’s Veterinary Drug Handbook. 8th ed. Stockholm, WI: profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Wiley-Blackwell. 2015. Pharmacol Ther. 2012;35(7):745-767.

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